Our data show that TLR1, and more specifically the nonsynonymous T1805G variant (I602S), is the genuine target of positive selection detected in the TLR10-TLR1-TLR6 gene cluster in Europeans. First, TLR1 is ~2 times more diverse in non-African than in African populations, a pattern not compatible with the African origin of modern humans…This pattern has been observed only once among the 323 genes (0.3%) sequenced by the Seattle SNP consortium. Thus, the increased diversity observed in TLR1 among non-Africans probably results from ongoing hitchhiking between the selected allele and neutral variation at linked sites. Second, the 1805G (602S) mutation presents the highest level of population differentiation (FST = 0.54) of all SNPs located in this gene cluster…Third, among the three nonsynonymous variants composing the haplotype identified as being under positive selection in Europeans (H34, see Figure S5), only the TLR1 1805G (602S) variant has a remarkable impairment effect on agonist-induced NF-ÎºB activation, showing a decreased signaling by up to 60%…These findings are consistent with previous studies showing that, homozygous, and to a lesser extent heterozygous, individuals for the 1805G allele present impaired TLR1-mediated immune responses after whole blood stimulation …Taken together, it is tempting to speculate that an attenuated TLR1-mediated signaling, and a consequently reduced inflammatory response, has conferred a selective advantage in Europeans – a scenario that would explain the very high frequency (51%) of the “hypo-responsiveness” T1805G mutation in Europe. This observation raises questions about the possible evolutionary conflict between developing optimal mechanisms of pathogen recognition by TLRs, and more generally PRRs, and avoiding an excessive inflammatory response that can be harmful for the host.

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In what context could a *reduced* inflammatory response generate such a strong signal of selection? Unless I’m misreading the summary, the statistics suggest a pretty noticeable difference in fitness. Could this be part of the adaptation to a wheat-based diet? Less severe gluten intolerance / celiac disease for those that have the novel variant?

– Activated Vitamin D (the 1,25-dihydroxy form) interacts with the TLRs and with the adaptive immune system, and eco-evolutionary changes in the D system in northern peoples may perturb the fitness landscape for the TLRs.

– There may be a trade-off between somes aspects of infection resistance and the incidence of, not just celiac disease, but all fitness-lowering immune activation or immune tone states. (Some such states could be subclinical and perceived by us as normal variation. For example, the proinflammatory cytokine TNF-alpha has a baseline expression in the absence of any overt infections, and the TNF knockout mouse was found to have a much higher proclivity for spontaneous exercise.)

– Further to the above, there may be certain acute situations where inflammation kills you and a weaker response would be better. As I recall there may be some indications that the Spanish Flu fits this description.

– “TLR1 also heterodimerizes with TLR4, not to enhance its function, but rather to inhibit TLR4 activity.” But this group didn’t study the function of the derived allele in the TLR1/4 heterodimer. It’s possible the fitness gain may occur through that dimer.

– Getting outside the box, and kind of just making stuff up now, the acne bacterium is gram-positive and thus may well be sensed by the TLR1/2 heterodimer, and who knows whether this does any good or just promotes visible acne? Even though acne does not reduce vigor or fertility, the human brain “thinks” it does and thus acne is quite significantly fitness-reducing via sexual selection. In time, the brain could learn to distinguish between acne and leprosy, etc, and thus stop finding acne unattractive – but this might take a really long time. Freckles are interesting in this connection – at moments I find them almost a little repulsive, presumably because they resemble a skin disease, and yet in the end I find them attractive… relatedly I’m very NW European ethnically, and insane about redheads (who are often freckled), as was my grandfather. Probably a vitamin D thing.

– Getting way way out there into deep speculation space, imagine a Cochran-Hawks scenario for some of the gram-positive commensals that sometimes cause disease but usually don’t (strep, staph, etc). I’m not sure exactly what the significances of the disease states are; they may actually at times be fitness-reducing for the bacteria. It seems like being in cities should make them more virulent, but if their populations skyrocketed along with man’s, the greater supply of new mutations may have helped them get along better with their hosts, thus reducing pressure to maintain TLR1 at fully inflammogenic fuctionality. Or, man may have developed other new mutations that helped keep these bacteria in line, which could also free up TLR1.

“Here we show that herpesvirus latency also confers a surprising benefit to the host. Mice latently infected with either murine gammaherpesvirus 68 or murine cytomegalovirus, which are genetically highly similar to the human pathogens Epstein?Barr virus and human cytomegalovirus2, respectively, are resistant to infection with the bacterial pathogens Listeria monocytogenes and Yersinia pestis. Latency-induced protection is not antigen specific but involves prolonged production of the antiviral cytokine interferon-gamma and systemic activation of macrophages. Latency thereby upregulates the basal activation state of innate immunity against subsequent infections. We speculate that herpesvirus latency may also sculpt the immune response to self and environmental antigens through establishment of a polarized cytokine environment.”

I have a printout of this paper, somewhere. The improbably named Herbert W. “Skip” Virgin IV is not kidding about the resistance to L monocytogenes and Y pestis: the viruses up-mod the median infective doses of these bacteria by multiple orders of magnitude – maybe three, if I recall.

It’s possible some near-commensal organism may have recently become near-universal in eurasian and post-eurasian humans. This could alter the immune function and change the fitness landscape for TLR-1. Presumably, if some population of mice were to be cured of these common herpesviruses – yet were still in danger from Y pestis, L monocytogenes, and all the other varmints – they would evolve higher baseline immune tone.

Randall mentioned something about entrepreneurs possibly being hypomanic. It’s possible low baseline immune tone might have something to do with this. Such a phenotype would be superior today; in the past it would have been a mixed blessing because of higher energy use and greater vulnerability to infection. As I mentioned, the TNF-a knockout mouse spontaneously runs on exercise wheels much more than wild type.